Synthesis of vitamin a



Patented Feb. 13, 1945 UNITED STATES' PATENT OFFICE SYNTHESIS OF VITAMIN A Nicholas A. Milas, Belmont, Mam, assignor to Research Corporation, New York, N. Y., a corporation of New York No Drawing. Application March 3, 1942,- Scriai No. 433,226

8 Claims.

The general object of the present invention is to provide a novel process for the synthetic production of vitamin A and a number of related intermediate products.

The accepted chemical structure of vitamin is represented by the formula:

Eommon A CH: cm

CICHCOOCQHI NaO CsHs B-xonone CH: CH:

H CH:

Compound II Other alkali alcoholates advantageously may be used in this condensation provided they are free from alcohols.

The reaction of Equation A is understood to involve two reactions which proceed simultaneously or successively, i. e. the combination of the fl-ionone and the ethyl chloroacetate forming the compound CH1 CH3 Compound Ho which reacts with the sodium ethylate yielding Compound II.

In the second step, Compound II is saponified with 10% alcoholic potash and the resulting glycidic acid, Compound III, Equation B, is separated and decarboxylated by distillation to produce 1-[2',6',6'-trimethyl cyclohexen-1'-yl]-3- methyl buten-1-al-4, Compound IV, Equation C.

Eouarrou B CH: CH:

OH: H H 4: H KOH H C=C -CCOOH Com and 11+ Do Alcohol Compound III Eons-non C CH! CH;

Distillation H l H CH:

Compound IV Compound IV may be prepared also by con- (lensing, in an ethereal solution, s-ionone with ethyl dichloroacetate (ClaCHCOOCzI-Is) in the presence of dilute magnesium amalgam, yielding Compound IIa, Equation D, which latter may be saponiiied with alcoholic potash and the resulting saponiflcation produce decarboxylated to Product IV as in Equations B and C.

EQUATION D CH: CH;

GliCHC O 0 Can! H p-ionone Compound IIa Here it will be seen that Compound IIa is identical with the intermediate product of Equation A and when this Product 11a is subjected to saponiflcation with alcoholic KOH as in Equation B, it is simultaneously or successively converted into Compound II and Compound III.

Instead of decarboxylating Compound III by distillation as described above, Compound III is mixed with two molecular equivalents of pyridine and the resulting pyridine salt distilled under a pressure of about 1 mm. and the fraction distilling at about from C. to 103 C. (Compound IVa) collected. This fraction (Compound IVa) serves in the remainder of the process described hereinafter in the same way as Compound IV but evidence, such as its boiling point, spectroscopic examination, and absence aldehydic properties, indicates that it is not Compound IV but a compound of the formula.

CH: CH: C

H H H H -C=C -CH O H CH:

Compound IVa In the third step, Compound IV or Compound No is condensed with sodium or lithium acetylide in a mixture of anhydrous ether and liquid ammonia at temperatures between -55 and 70 C. After the reaction is over, the ammonia is removed and the product treated with a dilute solution 01' tartaric acid, although aqueous solutions of ammonium sulfate, ammonium chride or other organic acids may also be used.

Th resulting Compound V or Compound Va, Equations E and Ea, is extracted from this mixture in an impure state and may be purified either by high vacuum distillation in an inert atmosphere or by preparing its phthalic acid ester by reacting the mixture with phthallc anhydride in pyridine solution. The phthalic acid ester is subsequently saponified to obtain the pure acet- Compound Va It will be observed that Compounds V and Va are identical excepting that the positions of the hydrogen atom and the hydroxyl group on the third and fourth carbon atoms of the side chain counting from left to right are reversed.

Compound V or Compound Va may be prepared also (see Equation F) by the interaction of the mono-Grignard of acetylene (HCECMgX) and Compound IV or Compound IVa, respectively. Eqnarron' F CompoundIV HCECMgX CompoundV or o 0! Compound IVs (X stands for halogen) Compound Va In the fourth step, Compound V or Va may be dehydrated by distilling under high vacuum with small amounts oi naphthalen sultonic acid or p-toluene sulfonic acid yielding Compound VII directly (see Equation G).

Eqnsrron G vacuum or Compound Va distillation dehydrating catalysts Thus it will be seen that both Compounds IV and Na may be treated in the same manner t yield Com-pound VII.

Compound V Compound VII (see equation I) ylene carbinols, Compound V or Com-pound Va.

Eoua'rron E cm CH:

CH; H n J: n NaCECH H o= -oczcn Compound IV+ s 4) inliquid NH: Hy-CH; H

Gampound V Eouarron Ea cm cm on,

n n n NaCECH H c=c- -c-c-=-on CompoundIVo --o H inliquid NH;

However, better yields of Compound VII are obtained by preparing from Compounds V and Va the halides thereof, Compounds VI and Wu. Equations H and Ha, and subsequently removing hydrogen halide with alcoholic potash (see Equations I and Ia) Compound VIa It is observed that Equation Ha works best with the chloride, less well with the bromide, and poorly or not at all with the iodide.

Eonsrron I CH: OH:

alcohol Compound VII Eova'rron IA KOH Compound VIo+ -r CompoundVII alcohol Still another method of converting Compound V or Compound Va into Compound VII is to form the Grignard of Compound V having the formula CH CH:

OH; H H 4: H H C= H-CCECMgX I CMgX H CH2 Grionard of Compound V (X stands for halogen) or the Grignard of Compound "Va having the formula CH: CH;

H H: i C H C Grim: *ofCom und vh (X stands for halogen) 1 29 and mix either of said Grignard coinpounds'wi th exactly one mol of CH: v BIO-04GB:

and distill the mixture under a high vacuum.

In the fifth step the Grignard or alkali metal acetylide of Compound VII is prepared by allowing it to react in ether solution with ethyl mag-.

nesium bromide or metallic lithium, for example:

To the Grignard or alkali acetylide of Compound VII is slowly added methyl vinyl ketone (alias) whereby the Product VIII is formed (see equation J).

BYOB: I

Compound VIII EQUATION K H Compound vm+ Pd or active iron CH: CH:

\/ H: CH

H H H In the seventh step, Compound IX may be treated with acetic anhydride to form the acetic ester of vitamin A, Compound XI, Equation L.

In this step any suitable acid anhydride other than acetic anhydride, such as propionic and its higher homologues up to and including palmitic and stearic and other organic acid anhydrides, such as benzoic acid anhydride, could be employed to produce the corresponding vitamin A esters, any of which may be converted into vitamin A by saponification, as described hereinafter.

EQUATION L acetic anhydride CompoundIX Compound XI (see Equation N) Better yields of the acetate are obtained when Compound IX is treated first with a halogenating agent such as phosphorus tribromide in pyridine yielding Compound X, Equation M, which latter is treated with potassium acetate yielding Compound XI, Equation N.

In this step Compound IX may be treated with any other suitable halogenating agent such as phosphorus trichloride or thionyl chloride and the resulting halogen Compound X converted into any desired organic acid ester of vitamin A by treating it with'the alkali metal salt of the desired acid in the presence of the free acid.

Still another method of making the esters of vitamin A is to treat Compound XV or Compound XVa with acetic or any other suitable organic acid anhydride in the presence of the alkali metal salt of said acid and heat the mixture in vacuum thereby directly producing the acid ester of vitamin A.

EQUATION M CH: CH: CHI

PX: Compound IX+ ------s H Py dine I (in which X stands for halogen) Compound X EQUATION N Potassium acetate Compound 11-!- heat Compound XI The vitamin is finally prepared by saponifying Compound XI, Equation 0, or by treating Compound X with silver hydroxide (see Equation P).

EQUATION O saponliy -O alcoholic KOH -70" C. in N; atmosphere EQUATION P c d X+ AgOH om an -s p0 in alcoholic solution up to 50 0.

Compound XI+ Compound I Compound I acetylide in liquid'ammonia to produce Compound XI, Equation Q, which latter is then converted into the Grignard XIII, Equation R, by interaction with ethyl magnesium bromide. The

Grignard XII is allowed to react in ether solution with the Compound IV Or IVa followed by hydrolysis with tartaric acid or ammonium sulfate to produce Compound XIV or XIVa, Equation S or Sa.

EQUATION Q OH: H t H,c=c- 42511 -D in liquid NH;

Compound XII EQUATION R Compound XII+ 25 Compound or a is then partially reduced to Copound XV or a using the cata-l lysts'and conditions described above (see E na TEL' 3O EQUAHQI? T o mponnd m H8 Pd on CaCGn or BaSOo Compound XV R OompoundXIVa =-l catalyst Cbrlpoumi XVa An alternative method used to prepare Compound XIV or XlVa consists in the interaction of the Grignard of V or Va with methyl vinylketone (see Equations U and Ua),

4 asoareo Eousrxou 8 Eoumon Us mnowod by Grlgnard of Va hydrolysis with Compound IV+Oomponnd -z or (NHdaSO; 5 H c. c=cu x+ on, on, on, on, mx

B n n i n n n c==c- -c-cso- -c=c I n H H H m on. Ely-CH3 O=1-CH=CH. -0 XIVa (X stands fol-halogen) Compound xrv Compound XV or XVa is halogenated with a 7 followed by 16 suitable agent such as a phosphorus trihalide, e. 3. Compound Iva CompoundXIII- phosphorus trichloride or tribromlde in pyridine at 0 C. yielding Compound XVI or XVIa, Equations W and Wu, and the latter are dehydrobalo- H H l H CHa H genated, for example, by treating with exactly H 20 one mol of potassium. hydroxide in alcohol to I H H H yield Compound x, Equation Y. 11 cm Eermrron W a %P a CompoandXIYa Pyridine at 0 C.

(in which X stands for halogen) Compound XVI Emission a %PXa 9 Pyridine at 0 0.

3H; CH1:

H C-CHX (in which X stands for halogen) Compound XVIB (The above reactions work better with the chloride than with the bromide.)

KOH ---e Compound X or alcohol VIo Pnmnumrron or Gnrcm Esrnn COMPOUND II, Fmsr STEP, EQUATION A Twenty-four grams of metallic sodium is dissolved in about 300400 cc. of absolute ethyl alcohol in a one liter filter flask fitted with a reflux condenser. It has been found preferable to add all of the sodium at once and after it has gone into solution, the alcohol is removed under reduced pressure at temperatures ranging from ISO-170. A white sodium ethylate results. This is added slowly to a vigorously stirred mixture of 192 grams of fl-ionone, 122 grams ethyl chloroacetate and 110 cc. of anhydrous toluene (benzene mayalso be used) at 0". After all of the sodium ethylate has been added, stirring is continued until the mixture becomes homogeneous and brownish in color, then allowed to stand at room temperature for '7-10 hours. .It is then heated on the water bath for 5 hours, cooled to room temperature and acidified with 25% acetic acid. The oil separating from this mixture is fractionated under reduced pressure and the fraction boiling at 152-155 (2-3 mm.) collected. A

yield of about 80% of Compound II is obtained. 6

Pnnrmrron or Conrormns lII AND IV, Slcorm Srzr, Eomrrons B AND C 'To obtain Compound III, 10"! g. of Compound II is mixed with one equivalent (21.6 g.) of 10% o alcoholic potash and the mixture heated on the water bath for about two hours. The alcohol is then removed under reduced pressure and the residue dissolved in the minimum amount of water and the aqueous mixture extracted a few extract is then dried with anhydrous magnesium 2 sulfate, filtered and the ether removed under reduced pressure. The residue (Compound III) is heated in an atmosphere of nitrogen and in the presence of powdered glass or flnely divided copper to facilitate the removal of carbon dioxide and the aldehyde formed finally fractionated under reduced pressure and the fraction boiling at 143-145 (5 mm.) collected. This has an n 1.5032 and forms a 2,4-dinitrophenylhydrazone; L

M. P. 155-157 having the correct combustion Synthesis of 1-[2',6',6'-trimeth1/l cyclohexen-P- yll-3-methyl 3-apozy butane-1. (Compound IVa) Compound I Va To a mixture of 245 g. (2 mols) of ethyl chloroo Pusrns'rron or Comrourms V AND VA, THIRD S'rsr,

acetate and 110 g. of anhydrous, sulfur-free toluene contained in a three-necked, round bottomed flask equipped with a mercury-sealed stirrer, a thermometer, and a calcium chloride tube and cooled to about add 19 g. (1 mol) of ionone. By means of a Gooch rubber connection introduce, over a period of two hours with rapid stirring, 46 g. (2 mols) of finely powdered sodium ethoxide free from alcohol. Bring the mixture slowly to room temperature by allowing it to stand overnight with moderate stirring in an atmosphere of nitrogen. Continue stirring while the mixture is heated in nitrogen on the Water bath for four hours, then cool to room temperature and neutralize with a solution of 167 g. of glacial acetic acid in 500 cc. of water. The mixture separates into two layers. Remove the nonaqueous layer andextract the aqueous layer with two 50 cc. portions of ether and combine the extracts with the non-aqueous layer. Remove the ether and the toluene and other low boiling constituents by subjecting the mixture to a vacuum distillation (10-20 mm.) in an atmosphere of nitrogen at the temperature of boiling water.

Cool the residue (Compound 11) to room temu perature and add toit 840 cc. of alcohol containing 85 g. of potassium hydroxide and reflux the resulting mixture in nitrogen for one hour under a slightly reduced pressure, then remove under reduced pressure approximately twothirds of the alcohol. Cool the residue and pour it into 1500 cc. of .deoxygenated water and extract the mixture successively with 500, 200 and 150 cc. of ether; combine the extracts and wash with 200 cc. of water andcombine the latter with the aqueous solution. Add to the aqueous layer 200 cc. on fresh ether and acidity with 654- cc. of 20% orthophosphoric acid. Remove ether layer and extract non-aqueous layer successively with 200 and cc. of ether and combine ether extracts; wash ether extracts twice with cc. portions of water, dry over anhydrous magnesium sulfate, filter and remove ether under reduced pressure. The residue consists of almost pure 0 glycidic acid (Compound 111) containing sma amounts of fl-ethoxy acetic acid.

To decarboxylate the glycidic acid dissolve it in 158 g. (2 mols) of pure anhydrous Py dine and subject the mixture to a vacuum distillation in an atmosphere of nitrogen. The pyridine comes over at lower temperatures, then, the residue is fractionated and the fraction boiling at 95-140 (2 mm.) I is collected and designated as the'crude portion of Compound IVa. This product is found to contain a small amount of an organic acid, and to remove the latter the product is dissolved in 250 cc. of ether and the ethereal solution shaken vigorously twice with 200 cc. of 5% sodium bicarbonate solution. The ethereal 35 solution is then dried over magnesium sulfate,

filtered, the ether removed under reduced pressure and the residue fractionated using a Claisen flask attached to a 30 cm. Vigreux column and the fraction boiling at 90-103 (1-2 mm.) col- 0 lected. 11. 1.5110, 1125 0.940. -This product fails to give an aldehyde test with fuchsin reagent and absorption spectrum in the ultraviolet region of the spectrum fails to show the presence of an aldehyde group either isolated from or conjugated with the double bonds.

The large range in boiling point (90- 103) indicates the presence in the product of the cis and trans isomers. The boiling point of the major isomer is about 99 to 103.

EQUATIONS E AND EA To about 1 l. of liquid ammonia, in a 3-necked flask equipped with a Hershberg stirrer and a dropping funnel, was added 1 g. of hydrated ferric nitrate and l g. of metallic sodium and the mixture stirred for 1 hour while the temperature was kept at -55 to -70. To this mixture was then added a trifle excess over half a mol of metallic sodium and the mixture stirred for half an hour longer. Dry acetylene was then passed through the mixture for several hours or until most of the blue color had assumed a graywhite color. To this mixture was then added. in the course of three hours. 46 g. of Compound IV or Compound IVa in 200 cc. of anhydrous ether taking carethat the temperature of the mixture never rises above 60 and that the 70 stirring is very rapid. After all of the aldehyde or oxide had been added, the mixture is stirred for 24 hours longer, keeping the temperature between 55' and -70. The ammonia is then allowed to evaporate and the brownish residue treated with excess cold aqueous solution of dtartaric acid and the resulting mixtureextracted with ether from which the acetylene carbinol, Compound V or Compound Va, is isolated either by distillation under high vacuum (10" mm.) or by preparing its acid phthalate ester in anhydrous pyridine and subsequently saponifying this ester to obtain the pure acetylene carbinol. The phthalic acid esterhad the correct analysis and semi-micro-hydrogenation revealed the presence of 4 double bonds. The acetylene carbinol also gives a heavy whitish-gray precipitate with ammoniacal alcoholic silver nitrate solution characteristic for acetylenes.

Compounds V and Va have also been prepared, in anhydrous ether solution, by the interaction of Compounds IV and Na, with the mono-Grignard of acetylene (HCECMgX) (Equation F).

PREPARATION OF COMPOUNDS VI, VIA AND VII, FOURTH STEP, EQUATIONS H, HA AND I AND IA Five g. of Compound V or Va. is dissolved in about 15 g. of anhydrous pyridine and the mixture cooled between and 5 C. To this mixture is slowly added about 2.2 g. of phosphorus tribromide or a corresponding amount of phosphorus trichloride taking care that the temperature does not rise above 0. After half an hour of standing at 0, the mixture is warmed to about 60-'70 for 15 minutes, then, without separatin Compound VI or VIa, the mixture is treated with the calculated amount plus excess of 10% alcoholic potash. The mixture is heated on the water bath for half an hour, then poured in four times its volume of water. The aqueous mixture is then extracted several times with ether and the ethereal solution shaken a number of times with a solution of d-tartaric acid to remove the pyridine. Finally, the ether solution is dried over anhydrous magnesium sulfate, filtered, and the ether removed. The residue is nearly pure {Compound VII, although for further purification one can distill it under a very high vacuum.

Compound VII may also be prepared by distiiling Compound V or Va under reduced pressure (10 -10 mm.) in the presence of small amounts, 1 to 5%, of p-toluene sulfonic acid or naphthalene sulfonic acid (Equation G).

PREPARATION or COMPOUND VIII, FIFTH STEP, EQUATION J Five g. of Compound VII in 30 cc. of anhydrous ether is slowly added to an ethereal solution of the calculated amount of ethyl magnesium bromide and the mixture refluxed in an atmosphere of nitrogen for 5 to 10 hours. To this mixture is then slowly added at 0 with stirring about 2 g. of methyl vinyl ketone which is freshly distilled from small amounts of hydroquinone. The

and ammonium sulfate. After the Grignard mixture is completely hydrolyzed, the ethereal layer is separated and dried over anhydrous magnesium sulfate, filtered, and the ether removed under reduced pressure. The residue which is nearly pure Compound VIII may now be used for the next step.

For making Compound VIII from Compound VII via the alkali metal acetylide of Compound VII instead of the Grignard thereof, a mixture of equal parts of liquid ammonia and anhydrous ethyl ether is prepared and while being maintained at 60 to -70 C. small equivalent amounts of Compound VII dissolved in anhydrous ethyl ether and metallic lithium are added while rapidly stirring. After each addition, the blue color produced is permitted to completely disappear before another addition of Compound VII and lithium is made. After the desired amount of Compound VII and the equivalent amount of lithium have been dissolved, a solution of an equivalent quantity of methyl vinyl ketone in anhydrous ethyl ether is added dropwise, in the course of an hour, with continued stirring and while maintaining the temperature at -60 to 'I0 C. The stirring and maintenance of the temperature of -60 to -70 C is then continued for about 10 hours, after which the temperature is allowed to rise and the ammonia to evaporate. The reaction mixture is then neutralized with tartaric acid dissolved in ice cold water and the resulting mixture extracted several times with ethyl ether. The combined ether extracts are dried with anhydrous magnesium sulfate, then filtered, the ether evaporated under reduced pressure and the residue subjected to a vacuum of from 10- to 10- mm. of mercury to vaporize and remove unreacted Compound VII and methyl vinyl ketone. The residue of this last treatment, on analysis, conforms to the formula of Compound VIII.

PREPARATION OF COMPOUND IX, SIxTII STEP, EQUATION K Compound VIII is dissolved in absolute alcohol and to the solution added about one-twentieth of the weight of Compound VIII of 1% palladium black deposited on solid powdered carbonate made in accordance with methods described in the literature. Barium sulfate may be advantageously used as the support of the catalyst. The calculated amount of hydrogen to saturate one of the bonds of the triple bond is then allowed to be absorbed by the system. The mixture is then filtered and the filtrate distilled under moderately'reduced pressure. The residue is nearly pure compound IX.

The reduction of Compound VIII to Compound IX may also be accomplished under 50-75 atmospheres of hydrogen at not higher than C. and in the presence of an active iron catalyst prepared by leaching the aluminum from an iron-aluminum alloy (Equation, K).

PREPARATION OF COMPOUND XI, SEVENTH STEP, EQUATIONS M AND N Although Compound XI may be prepared by the treatment of Compound IX with acetic anhydride (Equation L), better yields are obtained by dissolving Compound IX in anhydrous pyridine, cooling to 0, and adding the calculated amount of phosphorus tri bromide, Equation M, taking care that the temperature does not rise above 0. The mixture is then warmed to room temperature and kept there for two hours. The mixture is then dissolved in ether and the ethereal solution extracted with a cold 25% solution of acetic acid to remove the pyridine and the phosphorous acid. After the ethereal solution is dried over anhydrous magnesium sulfate, and filtered, the ether is removed under reduced pressure and the residue Compound X, Equation M, is dissolved in glacial acetic acidand treated, in an atmosphereof nitrogen, with freshly fused potassium acetate, EquationN. The mixture is gently heated for about 2 hours to not higher than 100 C., then poured in cold water and ex-- tracted with ether. The ethereal solution is separated, dried, and the ether removed. The residue contains considerable amount of Compound 2,see,1eo 7 XI from which vitamin A can be easily pre-, and containing the linkage pared by saponifying it in the usual manner with alcoholic potash (Equation 9). However, Com- H H 1 pound XI may be used directly as a vitamin A H substitute. I l l This application is a continuation-in-part of H p my application Serial No. 353,775, filed August 22, 1940.

I claim:

1. Process for decarboxylation which comprises mixing a compound of the formula CH; CH

with about 2' molecular proportions of pyridine, distilling the resulting-mixture under a pressure of about 1 mm. of mercury and collecting the fraction which boils at a temperature of from about 99 C. to 103 C.

2. In a process for decarboxylation, the step which consists in mixing a compound of the formula CH: CH;

with pyridine, distilling the mixture under reduced pressure, and collecting a fraction including a compound of the formula CH; CH;

H I OH:

pressure of about 1 mm. of mercury.

4. As arnew product, a compound of the for- .mula CH; CH:

CH: n n 5 n H C=C- CH 0 CHI which has the following properties: B. P. 99 to- 103-C. (1-2 mm.); u 1.5110; dasq 0.940; negative aldehyde test with fuchsi'n reagent which is in conformity with its absorption spectrum in the ultra-violet region.

5. As a new productiaicompound having the empirical formula CuHzsO said compound being a liquid at room temperature and distilling within the range from C. to 103 C. at a pressure of 1 to 2 mm. of mercury and having the following characteristics: 11 1.5110, dis-= 0.940, ab'sence of aldehyde test with fuchsin reagent and absence of aldehyde indication in the absorption spectrum in the ultraviolet light region.

6. A process for the production of the com- P und of the formula H I OH:

which comprises decarboxylating a salt of the glycidic acid of the formula CH CH with an organic base. I 7. A process for the production of the formula CH: CE:

I of a compound which comprises pyrolyzing the saltof the glycidic acid of the formula CH: CH

which comprises preparing a salt of the said compound with an excess 01 an organic base and pyrolyzing this salt under a pressure of 1 mm. of mercury and temperatures ranging between -160 C. and collecting the fraction which boils at a temperature of about 00' C. to 108 C.

NICHOLAS A. MILAS. 

